Hydrophobic active ingredients, such as progesterone, cyclosporin, itraconazole and glyburide present delivery challenges due to their poor aqueous solubility and slow dissolution rate. Several commercial products of these hydrophobic drugs are available, the various products using different methods to try to enhance in vivo performance. One approach is size reduction by micronization, such as in Prometrium (micronized progesterone) and Micronase (micronized glyburide). Other approaches include size reduction in emulsion formulations, such as in Sandimmune (cyclosporin emulsion) and NeOral (cyclosporin microemulsion). These approaches suffer from several disadvantages. Micronization/nanonization presents processing and stability challenges, as well as dissolution limitations, since the micronized/nanosized drug still possesses a high degree of crystallinity. Liquid formulations present drug precipitation and packaging challenges, due to solvent evaporation. Moreover, non-solid formulations are more prone to chemical instability and capsule-shell incompatibility, leading to the possibility of leakage upon storage.
For hydrophilic active ingredients, the formulation challenges are different. Although these compounds are readily soluble in the aqueous gastrointestinal environment, they are poorly absorbed, due to poor membrane permeability and/or enzymatic degradation. Surfactants and lipophilic additives have been reported to improve membrane permeability; see, e.g., LeCluyse and Sutton, “In vitro models for selection of development candidates. Permeability studies to define mechanisms of absorption enhancement,” Advanced Drug Delivery Reviews, 23, 163-183 (1997). However, these compositions fail to maintain effective levels and type of enhancers for bioacceptable absorption enhancement. Most solid dosage forms of hydrophilic active ingredients exhibit poor or no absorption of the active. Moreover, these non-solid formulations suffer from the disadvantages of chemical instability, leakage and capsule shell incompatibility as discussed above.
Solid carriers for pharmaceutical active ingredients offer potential advantages over micronized drugs, emulsions or solubilized formulations. Solid carriers, typically of size less than about 2 mm, can easily pass through the stomach, thus making the performance less prone to gastric emptying variability. Further, the problems of leakage and other disadvantages of liquid formulations are not present in solid carrier formulations. To date, however, such solid carrier formulations generally have been limited to a few specific drugs, due to difficulties in formulating appropriate drug/excipient compositions to effectively coat the active ingredient onto a carrier particle.
Conventional solid dosage forms of hydrophobic active ingredients, such as tablets, or multiparticulates in capsules, often exhibit slow and incomplete dissolution and subsequent absorption. These formulations often show a high propensity for biovariability and food interactions of the active ingredient, resulting in restrictive compliance/labeling requirements.
Due to the slow dissolution and dependence on gastric emptying, solid dosage forms often delay the onset of some hydrophobic active ingredients.
Thus, there is a need for pharmaceutical compositions and dosage forms, and methods therefor, that do not suffer from the foregoing disadvantages.